Organocatalyzed three-component Ugi and passerini reactions of 4-oxoazetidine-2-carbaldehydes and azetidine-2,3-diones. Application to the synthesis of γ-lactams and γ-lactones

Article abstract of DOI:10.1021/jo4015358

The organocatalyzed U-3CR of 4-oxoazetidine-2-carbaldehydes has been studied. In addition, the organocatalyzed P-3CR of 4-oxoazetidine-2- carbaldehydes and azetidine-2,3-diones has been described for the first time. U-3CR and P-3CR adducts have been obtained in good yields and reasonable diastereoselectivities. Phenyl phosphinic acid has been the catalyst of choice to study the scope of both organocatalyzed multicomponent reactions using a variety of β-lactams, isocyanides, and amines. Highly functionalized U-3CR and P-3CR adducts derived from β-lactams have proved to be useful substrates for the preparation of enantiopure γ-lactams and γ-lactones via N1-C2 β-lactam ring opening/cyclization under acidic or basic conditions.

Full text of DOI:10.1021/jo4015358

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Article
Organocatalyzed Three-Component Ugi and Passerini Reactions
of 4-Oxoazetidine-2-carbaldehydes and Azetidine-2,3-diones.
Application to the Synthesis of gamma-Lactams and gamma-Lactones
Benito Alcaide, Pedro Almendros, Cristina Aragoncillo, Ricardo Callejo, and María Pilar Ruiz
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 16 Sep 2013
Downloaded from http://pubs.acs.org on September 17, 2013
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Organocatalyzed Three-Component Ugi and Passerini Reactions of 4-Oxoazetidine-2-
carbaldehydes and Azetidine-2,3-diones. Application to the Synthesis of γ-Lactams and γ-
Lactones
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Benito Alcaide,*, † Pedro Almendros,‡ Cristina Aragoncillo,† Ricardo Callejo,† and M. Pilar Ruiz†
†Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Orgánica I, Unidad
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Asociada al CSIC, Facultad de Química, Universidad Complutense de Madrid, 28040-Madrid, Spain,
‡Instituto de Química Orgánica General, IQOG, CSIC, Juan de la Cierva 3, 28006-Madrid, Spain, and
alcaideb@quim.ucm.es
ABSTRACT
X
R2
NHR1
NHR3
H H
N
"ring-opening"
"cyclization"
H
H
N
R2
NHR3
R2
"U-3CR"
"P-3CR"
CHO
R1
O
O
PhP(OH)2 (cat.)
X
O
R1
O
O
2 for: R4NH2, X = NHR4
3 for: H2O, X = OH
6 X = NR4
7 X = O
1
O
O
O
O
H
HO
H
N
O
O
O
"P-3CR"
R2HN
N
PhP(OH)2 (cat.)
R1
O
R1
4
syn-5
Organocatalyzed U-3CR of 4-oxoazetidine-2-carbaldehydes has been studied. Besides, the
organocatalyzed P-3CR of 4-oxoazetidine-2-carbaldehydes and azetidine-2,3-diones has been described
for the first time. U-3CR and P-3CR adducts have been obtained in good yields and reasonable
diastereoselectivities. Phenyl phosphinic acid has been the catalyst of choice to study the scope of both
organocatalyzed multicomponent reactions using a variety of β-lactams, isocyanides and amines. Highly
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functionalized U-3CR and P-3CR adducts derived from β-lactams have proved to be useful substrates
for the preparation of enantiopure γ-lactams and γ-lactones via N1−C2 β-lactam ring
opening/cyclization under acidic or basic conditions.
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INTRODUCTION
Multicomponent reactions (MCRs) are synthetic processes that combine three or more substrates to
afford new compounds in one pot.1 This powerful methodology allows both complexity and diversity in
the final substrates with high atom economy. The advantages and the applications of MCRs have been
widely demonstrated in the synthesis of natural products2,3 and medicinal chemistry.3,4 In particular,
isocyanide-based MCRs (IMCRs) are especially attractive in terms of functional group tolerance and the
high levels of chemo-, regio-, and stereoselectivity obtained.5 Among them, the Passerini three-
component reaction (P-3CR) and the Ugi four-component reaction (U-4CR) are the most prominent. In
this context, List has reported the first organocatalyzed three-component Ugi reaction (U-3CR) of
different aldehydes, p-anisidine and a variety of isocyanides using phenyl phosphinic acid as catalyst.6
On the other hand, the β-lactam ring has been permanently associated with their potent antibacterial
activity and, more recently, with enzyme inhibition, anticancer activity and gene activation.7 Besides,
from the synthetic point of view, this four-membered ring is an excellent substrate to obtain a diverse
family of nitrogenated compounds ranging from three-membered skeletons to macrocyclic structures
and acyclic compounds.8 In particular, different methodologies which involves ring opening of the β-
lactam nucleus followed by cyclization have been developed.9
The γ-lactam ring is present in natural and synthetic products with interesting therapeutic
activities.10 For example, succinimide11 and pyroglutamic acid12 cores have significant chemical and
medicinal importance as they are implicate in different relevant processes. In addition, the γ-lactone
moiety is a substructure present in natural compounds. In particular N-acyl homoserine lactones (AHLs)
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are involved in the multicellular communication network of most gram-negative bacteria,13 and
sesquiterpene lactones exhibit a variety of biological activities.14
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Following up our interest in the area of the synthesis of nitrogenated compounds,15 and the
investigation of methodologies based in multicomponent processes,16 we became interested in the study
of the organocatalyzed U-3CR process in β-lactam substrates.
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RESULTS AND DISCUSSION
U-3CR of 4-Oxoazetidine-2-carbaldehydes
First of all, we decided to investigate the U-3CR catalyzed by phenyl phosphinic acid of 4-
oxoazetidine-2-carbaldehydes 1.
Starting substrates, optically pure 4-oxoazetidine-2-carbaldehydes 1a−e, were prepared, using
standard
methodology,
as
single
cis-enantiomers
from
imines
with the
of
(R)-2,3-O-
isopropylideneglyceraldehyde,
through
Staudinger reaction
corresponding
alkoxy(aryloxy)acetyl chloride in the presence of Et3N, followed by sequential acidic acetonide
hydrolysis and oxidative cleavage.17
In order to show the viability of the organocatalyzed U-3CR of β-lactam aldehydes 1, our first
experiment was the reaction of aldehyde 1a, allylamine and benzyl isocyanide (BnNC) in presence of a
catalytic amount of phenyl phosphinic acid (10% mol), using the same reaction conditions previously
described (toluene, 80°C).6 In the event, α-amino amide 2a was obtained as a separable mixture of
syn/anti isomers in 61:39 ratio in 83% yield (Table 1, entry 1). Compound 2a was also obtained
quantitatively within the same syn/anti ratio when the reaction was tested under milder conditions,
dichloromethane at room temperature (Table 1, entry 2). Thus, the above mild reaction conditions were
applied to study the scope of the multicomponent process of β-lactam aldehydes 1. The reaction of
aldehyde 1a, allylamine and t-butyl isocyanide (t-BuNC) in presence of phenyl phosphinic acid (10%
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mol) afforded product 2b with similar diastereoselectivity (63:37) and excellent yield (92%) (Table 1,
entry 3). When the U-3CR was tested in aldehyde 1b, with an aliphatic substituent in the nitrogen,
compound 2c was obtained with slightly better diastereoselectivity (72:28) in 66% yield (Table 1, entry
4). Analogously, the reaction of aldehyde 1c, t-BuNC and methyl glycinate, afforded compound 2d with
a comparable diastereoselectivity (70:30) and good yield (74%) (Table 1, entry 5). Unfortunately, α-
amino amide 2d was isolated as an inseparable mixture of syn/anti isomers. Next, we decided to explore
the multicomponent reaction using aromatic amines. The reactions were performed using aldehydes 1a
and 1d, benzyl isocyanide and t-BuNC, respectively, and an electron rich aromatic amine, p-anisidine.
Thus, compounds 2e and 2f were obtained with comparable values in terms of diastereoselectivity and
yield (Table 1, entries 6 and 7). However, α-(p-methoxyphenyl)amino amide 2e was isolated as an
inseparable mixture of syn/anti isomers. Compound 2g was obtained without significant changes in
terms of diastereoselectivity (68:32) and yield (67%) when the reaction was performed with aldehyde
1b, t-BuNC and an electron poor aromatic amine, such as p-nitroaniline (Table 1, entry 8).
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Table 1. U-3CR of 4-oxoazetidin-2-carbaldehydes 1, amines, isocyanides and phenyl phosphinic
acid as catalysta
NHR4
NHR4
H
H
N
R2
H
H
N
NHR3
H
H
N
R2
NHR3
R2
CHO
R1
PhP(OH)2 (10% mol)
conditions
R3NC
R4NH2
+
+
+
O
O
O
R1
O
R1
O
syn-2
1
anti-2
Entry Aldehyde R1
R2
R3
R4
Conditions
t (h)b Product syn/antic Yield (%)d
1
2
3
(+)-1a
(+)-1a
(+)-1a
PMPe
PMPe
PMPe
MeO Bn
MeO Bn
2-propenyl
2-propenyl
toluene/80°C 28
2a
2a
2b
61:39
61:39
63:37
51:32
61:39
58:34
CH2Cl2/rt
CH2Cl2/rt
28
48
MeO t-Bu 2-propenyl
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(−)-1b
(−)-1c
(+)-1a
(+)-1d
(−)-1b
2-propenyl PhO Bn
2-propenyl
CH2Cl2/rt
39
24
18
16
22
2c
2d
2e
2f
72:28
70:30
64:36
70:30
68:32
48:18
74h
Bn
Phtf
MeO t-Bu PMPe
PhO Bn
PMPe
t-Bu CH2CO2Meg CH2Cl2/rt
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PMPe
PMPe
CH2Cl2/rt
CH2Cl2/rt
CH2Cl2/rt
74h
62:28
2-propenyl PhO t-Bu PNPi
2g
46:21
aAll reactions were performed by using an aldehyde/amine/isocyanide ratio of 1.0:1.1:1.1 mmol. Reaction progress was
followed by TLC. The syn/anti ratio was determined by integration of well-resolved signals in the H NMR spectra (300
b
c
1
d
MHz) of the crude reaction mixtures before purification. Yield of pure, isolated isomers with correct analytical and
spectral data. ePMP = 4-MeOC6H4. fPht = Phtalimidoyl. gThe reaction was carried out by treatment of amine chlorhydrate
with triethyl amine in the reaction conditions. hYield of pure, isolated mixture of isomers. iPNP = 4-NO2C6H4.
Scheme 1 shows the mechanistic proposal for the U-3CR of compounds 1, which is comparable to
List’s proposal. Phenyl phosphinic acid I can be considered a Brönsted acid and, in the form of its
phenylphosphonous acid tautomer II, a Lewis base. Both properties could be involved in the catalytic
process. The mechanism proposed involves protonation of the in situ generated imine, formed by
reaction of aldehyde 1 and the corresponding amine. Next, addition of the isocyanide and subsequent
trapping of the nitrilium ion with the phosphinate anion would take place. Finally, a molecule of water,
which is released in the imine formation, reacts with intermediate IV to generate V, which fragments to
the α-amino amide 2, and the catalyst.
Scheme 1. Mechanistic proposal for the U-3CR catalyzed by phenyl phosphinic acid
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O
NHR4
Ph
P
H
OH
H
H
N
R2
NHR3
I
R4
H
O
R1
O
O
N
H
H
N
OH
H
H
N
R2
R2
R4NH2
Ph
P
2
H
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OH
II
R1
O
R1
O
1
R3NC
NHR4
NHR3
NHR4
H
H
H
R2
H
H
N
R1
R2
N
+
O
Ph
OH
O
R3
N
P
P
O
R1
Ph
HO
O
O
IV
V
H2O
P-3CR of 4-Oxoazetidine-2-carbaldehydes and Azetidine-2,3-diones
Once the U-3CR organocatalyzed by phenyl phosphinic acid was studied, we decided to investigate
the analogous process, the Passerini reaction of aldehydes 1. In fact, to the best of our knowledge, there
is no report about organocatalyzed diastereoselective Passerini reaction.18
According to the mechanism previously proposed for the organocatalyzed U-3CR, a molecule of
water is produced during the formation of the imine. Thus, an external addition of water would be
necessary which would act as the acidic component in the Passerini reaction. Taking into account this
idea, we decided to study the reaction of aldehyde 1a, t-BuNC, a stoichiometric amount of water and
phenyl phosphinic acid (10% mol) in dichloromethane at room temperature. Fortunately, the
corresponding α-hydroxy amide 3a was obtained as a mixture of isomers (60:40) quantitatively (Table
2, entry 1). Next, we decided to test the P-3CR in aqueous media in order to minimize the amount of
organic solvent employed. However, adduct 3a was isolated in lower yield (64 and 67%) when the
reaction was performed using mixtures of THF/H2O (1:1) and MeCN/H2O (1:1), respectively (Table 2,
entries 2 and 3). In addition, the reaction times for both experiments were considerably longer than with
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the use of dichloromethane as solvent. In relation with the diastereoselectivity, the use of MeCN/H2O
slightly decreased the syn/anti ratio (55:45) (Table 2, entry 3). Thus, we decide to study the scope of the
reaction using dichloromethane at room temperature. When the reaction was carried out with β-lactam
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1d, containing a phenoxy instead of a methoxy group at C-3 position of the β-lactam ring, the
diastereoselectivity was slightly increased (65:35) in the α-hydroxy amide 3b (Table 2, entry 4). Next,
we decided to investigate the effect of another isocyanide. Thus, the reaction of aldehyde 1a with
BnNC, water and phenyl phosphinic acid, in the above reaction conditions afforded compound 3b with
a comparable diastereoselectivity (60:40) and excellent yield (88%) (Table 2, entry 5).
Taking into consideration that the use of β-lactam aldehydes 1 with aliphatic substituents at nitrogen
position increased the diastereoselectivity in the U-3CR, we decided to examine the behaviour of
aldehydes 1c and 1e. In the event, the reaction of both compounds with t-BuNC and phenyl phosphinic
acid (10% mol) afforded adducts 3d and 3e respectively. Unexpectedly, compound 3d was isolated in a
very low diastereoselectivity (55:45) in 68% yield (Table 2, entry 6). Fortunately, an improved
diastereoselectivity (70:30) was observed for compound 3e, which was isolated in excellent yield (96%)
(Table 2, entry 7).
The structure of adducts 2 and 3 was assigned by NMR studies. The relative stereochemistry of
compounds 2 has been established in the γ-lactams (see below). However, NMR vicinal coupling
constants of the H4 and H4' protons for the syn-3 and anti-3 adducts are very useful information to
stablish the relative stereochemistry (see Table S1 in Supporting information). For any pair of
diastereomers, the vicinal coupling constant between H4 and H4' is higher for anti-isomers (3JH4,H4'
=
5.2−1.6 Hz) than for the syn-isomers (3JH4,H4' = 3.4−1.2 Hz). In addition, the stereochemistry of
compounds 3 was finally confirmed by chemical correlation with their corresponding γ-lactones (see
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below). Then, by analogy, adducts syn-2 are the major isomers for the previous U-3CR in aldehydes 1.
The observed syn-diastereoselectivity for compounds 2 and 3 might be explained by the Felkin-Anh
model.19
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Table 2. P-3CR of 4-oxoazetidine-2-carbaldehydes 1, isocyanides and water in presence of phenyl
Phosphinic Acida
OH
OH
H
H
N
R2
H
H
N
NHR3
H
H
N
R2
NHR3
R2
CHO
R1
PhP(OH)2 (10% mol)
solvent, RT
R3NC
H2O
+
+
+
O
O
O
R1
O
R1
O
syn-3
1
anti-3
Entry Aldehyde R1
R2
R3
Solvent
t (h)b Product syn/antic Yield (%)d
1
2
3
4
5
6
7
(+)-1a
(+)-1a
(+)-1a
(+)-1d
(+)-1a
(−)-1c
(+)-1e
PMPe
PMPe
PMPe
PMPe
PMPe
Bn
MeO t-Bu CH2Cl2
21
48
3a
3a
3a
3b
3c
3d
3e
60:40
60:40
55:45
65:35
60:40
55:45
70:30
60:40
38:26
37:30
59:32
55:35
37:31
67:29
MeO t-Bu THF/H2O
MeO t-Bu MeCN/H2O 32
PhO t-Bu CH2Cl2
MeO Bn CH2Cl2
Phtf
t-Bu CH2Cl2
19
20
21
20
2-Propynyl PhO t-Bu CH2Cl2
aAll reactions were performed by using an aldehyde/isocyanide/water ratio of 1.0:1.1:1.1 mmol.
c
bReaction progress was followed by TLC. The syn/anti ratio was determined by integration of well-
1
resolved signals in the H NMR spectra (300 MHz) of the crude reaction mixtures before purification.
dYield of pure, isolated isomers with correct analytical and spectral data. ePMP = 4-MeOC6H4.
The 3-substituted 3-hydroxy β-lactam scaffold is an efficient carboxylate mimic,20 showing
interesting activity in acyl CoA-cholesterol acyltransferase inhibition assays. In addition, it is found in
several monobactams with interesting pharmacological activities such as sulfacezin (A) (Figure 1), and
related compounds. Due to the importance of the 3-hydroxy-3-substituted β-lactam skeleton, we have
reported the synthesis of these compounds using different synthetic strategies.16,21
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O
Me
OH
H
H2N
N
N
H
N
CO2H
O
O
H
Figure 1. Sulfacezin (A), a representative example of a compound containing the 3-substituted 3-
hydroxy β-lactam framework.
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The results obtained with oxoazetidine-2-carbaldehydes 1 encouraged us to screen the P-3CR in
azetidine-2,3-diones 4. The starting materials, enantiopure azetidine-2,3-diones 4, were efficiently
prepared from aromatic or aliphatic (R)-2,3-O-isopropylideneglyceraldehyde-derived imines by
Staudinger reaction with acetoxyacetyl chloride in the presence of Et3N, followed by sequential
transesterification and Swern oxidation, as we have previously reported.22
First, we examined the reaction of azetidine-2,3-dione 4a with BnNC, water and phenyl phosphinic
acid (10% mol), affording α-hydroxy amide 5a with complete syn-diastereoselectively (with cis
configuration between the β-lactam H4 and the amide group on C3) and good yield (78%).
Analogously, the reaction of ketene 4b with BnNC and water, in the above reaction conditions afforded
3-substituted 3-hydroxy-β-lactam 5b in excellent yield and total diastereoselectivity. The reaction of
azetidine-2,3-diones 4a and 4d using t-BuNC afforded compounds 5c and 5d in total
diastereoselectivity although, compound 5c was isolated in low yield. The use of ethyl isocyanoacetate
with ketone 4a gave compound 5e with 45% yield and total diastereoselectivity.
The diastereoselectivity is controlled by the presence of the substituent placed at C-4 position of the
β-lactam ring, which blocks preferentially one face of the carbonyl group. Thus, the nucleophilic
addition takes place to the less hindered face of the carbonyl group, affording P-3CR adducts 3 as single
isomers.16a, 23
Table 3. P-3CR of azetidine-2,3-diones 4, isocyanides and water in presence of phenyl phosphinic
acida
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7
8
O
O
O
O
O
O
H
N
HO H
N
HO H
O
O
O
O
PhP(OH)2 (10% mol)
H2O
+
R2NC
+
+
R2HN
R2HN
solvent, RT
N
R1
R1
O
R1
O
9
anti-5
4
syn-5
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Entry Ketone R1
R2
t (h)b Product syn/antic Yield (%)d
1
2
3
4
5
(+)-4a PMPe
(−)-4b Bn
Bn
Bn
t-Bu
45
27
48
23
(−)-5a
(−)-5b
(−)-5c
(−)-5d
(+)-5e
100:0
100:0
100:0
100:0
100:0
78
80
48
71
45
(+)-4a PMPe
(−)-4c 2-propenyl t-Bu
(+)-4a PMPe
CH2CO2Et 72
aAll reactions were performed by using a ketone/isocyanide/water ratio of 1.0:1.1:1.1
b
c
mmol. Reaction progress was followed by TLC. The syn/anti ratio was determined by
1
integration of well-resolved signals in the H NMR spectra (300 MHz) of the crude
reaction mixtures before purification. dYield of pure, isolated isomers with correct
analytical and spectral data. ePMP = 4-MeOC6H4.
Synthesis of γ-Lactams and γ-Lactones via N1−C2 Ring Cleavage/Cyclization of U-3CR Adduct 2
and P-3CR Adduct 3, Respectively
Taking into account the importance of γ-lactam and γ-lactone skeletons, we decide to take advantage
of the highly functionalized adducts 2 and 3 to access to these 5-membered rings. In fact, rearrangement
reactions of both adduct would result a stereoselective synthetic pathway to functionalized γ-lactams 6
and γ-lactones 7 (Scheme 2).
Scheme 2. Possible N1−C2 β-lactam ring cleavage/cyclization of Ugi adducts 2 and Passerini
adducts 3
R3HN
N
O
R2
NHR1
O
R2
XH
O
X
O
R1
NHR3
6 (X = NR4)
7 (X = O)
2 (X = NR4)
3 (X = O)
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N1−C2 β-lactam ring cleavage/cyclization usually takes place in acidic or basic conditions. To
explore the process, compound syn-2a containing a p-methoxyphenyl group in the nitrogen of the β-
lactam was employed. It is well known that this kind of β-lactams undergo easy N1−C2 ring cleavage
due to the stabilization of the nitrogen anion, acting as a good leaving group. Treatment of adduct syn-
2a under acidic conditions, using a mixture of methanol and sulphuric acid, afforded γ-lactam syn-6a in
low yield (22%) (Scheme 3).
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60
Scheme 3. Synthesis of γ-lactam syn-6a via N1−C2 cleavage/cyclization in acidic conditions
MeO
O
NHPMP
NHBn
NH
H
H
N
MeO
NHBn
MeOH/H2SO4
RT, 54 h
(22%)
N
O
PMP
O
O
syn-(+)-6a
syn-(+)-2a
In order to improve the yield, we decided to carry out the reaction in basic conditions, using a
stoichiometric amount of sodium methoxide in methanol. Thus, reaction of compound syn-2a using one
equivalent of sodium methoxide in methanol at room temperature exclusively afforded γ-lactam syn-6a
in excellent yield (84%) after chromatographic purification (Table 1, entry 1). The reaction of isomer
anti-2a under the same reaction conditions gave the expected γ-lactam in 60% yield (Table 1, entry 2).
Fortunately, the feasible epimerization of the proton in α position of the amide group was not observed
in both experiments. The scope of the reaction was developed using Ugi adducts syn-2b and anti-2b,
with a t-butyl carbamoyl group, affording γ-lactams syn-6b and anti-6b in good yields (82 and 71%,
respectively). Interestingly, the expansion process took place with Ugi adducts syn-2c and anti-2c with a
propenyl group substituent in the nitrogen of the β-lactam ring. γ-Lactams syn-6c and anti-6c were
obtained in excellent yields (81 and 76% respectively) in longer reaction times. It seems reasonable that
the expansion reaction of N-propenyl substituted β-lactams can be slower than with N-PMP substituted
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β-lactams, because the negative charge of the nitrogen is not in resonance with the aliphatic group.
Next, the influence of an aromatic substituent in the amine group, such as p-methoxyphenyl, was
studied. Thus, reaction of an inseparable mixture of isomers 2e (syn:anti 64:36) in presence of sodium
methoxide and methanol at 35°C, gave β-lactams syn-6d and anti-6d as a separable mixture of
diastereoisomers by flash chromatography. Isomers syn-(+)-6d and anti-6d were isolated in good yields
and in the same syn/anti ratio (Table 1, entry 7). γ-Lactam syn-6e was obtained in lower yield (45%)
when the reaction was performed using compound syn-2f with a p-nitrophenyl group. It seems
reasonable that the nitrogen at this position is less nucleophile than in the rest of the examples.
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10
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Table 4. Synthesis of γ-lactams 6 via N1−C2 ring cleavage/cyclization of Ugi adducts 2a
R2
3
NHR1
NHR4
H
H
N
4
R2
NHR3
NHR3
MeONa/MeOH
RT
5
O
N
R4
O
O
O
R1
syn-6
R2
syn-2
NHR1
NHR4
H
H
N
3
4
R2
NHR3
NHR3
MeONa/MeOH
RT
5
O
N
R4
O
O
O
R1
anti-6
anti-2
Entry U-3CR adduct R1
R2
R3
R4
t(h)b Product
Yield (%)c
1
2
3
4
5
6
7e
syn-(+)-2a
anti-(+)-2a
syn-(+)-2b
anti-(+)-2b
syn-(+)-2c
anti-(+)-2c
2ef
PMPd
PMPd
PMPd
PMPd
MeO Bn
MeO Bn
2-propenyl 10
2-propenyl 10
syn-(+)-6a
anti-(−)-6a
syn-(+)-6b
anti-(−)-6b
syn-(+)-6c
anti-(+)-6c
84
60
82
71
81
76
MeO t-Bu 2-propenyl 23
MeO t-Bu 2-propenyl 23
2-propenyl PhO Bn
2-propenyl PhO Bn
2-propenyl 24
2-propenyl 24
17
PMPd
MeO t-Bu PMPd
syn-(+)-6d/anti-(+)-6d 51:28
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8e
syn-(+)-2f
2-propenyl PhO t-Bu PNPg
24
syn-(+)-6e
45
aAll reactions were performed by using a substrate/MeONa ratio of 1.0:1.0 mmol. Reaction progress was
followed by TLC. Yield of pure, isolated isomers with correct analytical and spectral data. PMP = 4-
b
c
d
e
f
9
MeOC6H4. The reaction was performed at 35°C. The starting material was an inseparable mixture of syn/anti
isomers in 64:36 ratio. gPNP = 4-NO2C6H4.
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13
14
Finally, it is important to remark that γ-lactams 6 with an amide group in C5 position, are
structurally related to pyroglutamic acid. Thus, compounds 6 are interesting compounds from the
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chemical and biological point of view.
Satisfied with the above results, we set out to evaluate the N1−C2 ring cleavage/cyclization of
Passerini adducts 3. The application of this methodology would allow access to γ-butyrolactones
(Tables 5 and 6). The FeCl3-catalyzed ring expansion reaction of 2-azetidinone-tethered allenic alcohols
to give γ-lactones has been recently described in our research group.24 Thus, we decided to apply the
same reaction conditions to substrate syn-3a. Reaction of α-hydroxy amide syn-3a, with FeCl3·6H2O
(10 % mol) in dichloroethane at 80 °C, selectively gave γ-lactone syn-7a in very low yield (23%) (Table
5, entry 1). Then, we decided to try the basic conditions used for the preparation of γ-lactams 6.
Reaction of compound syn-3a with 1 equivalent of sodium methoxide gave a mixture of γ-lactone syn-
7a (32%) and hydroxyamino ester 8 (47%) (Table 5, entry 2). The use of two equivalents of sodium
methoxide at room temperature or under reflux conditions, afforded hydroxyamino ester 8 exclusively
(75% and 48% respectively) (Table 5, entries 3 and 4). Unfortunately, the use of excess of sodium
methoxide gave compound 8 in lower yield, with partial epimerization after long reaction times.
Interestingly, when the reaction was conducted in a mixture of methanol and sulphuric acid gave
hydroxyamino ester 8 in good yield (73%) after chromatographic purification (Table 5, entry 5).
Table 5. Reactivity of α-hydroxy amide syn-3a
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OH
MeO
O
NHPMP
NHtBu
MeO
MeO2C
PMP
OH
H
H
N
MeO
NHtBu
Conditions
NHtBu
+
O
PMP
O
NH
(−)-8
O
O
O
syn-(+)-3a
syn-(+)-7a
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Entry Conditions
t(h)a syn-(+)-7a/(−)-8b Yield (%)c
1
2
3
4
5
FeCl3·6H2O (10% mol)/DCE/80 °C 21
100:0
40:60
0:100
0:100
0:100
23
MeONa (1 equiv.)/MeOH/RT
MeONa (2 equiv.)/MeOH/RT
MeONa (1 equiv.)/MeOH/reflux
MeOH (1 equiv.)/H2SO4 (2:1)
6
3
1
2
32:47
75
48
73
aReaction progress was followed by TLC. The syn/anti ratio was determined by
integration of well-resolved signals in the H NMR spectra (300 MHz) of the crude
reaction mixtures before purification. Yield of pure, isolated isomers with correct
analytical and spectral data.
b
1
c
Due to the difficulties to obtain γ-lactones in a one pot process from α-hydroxy amides 3, we
decided to prepare these compounds via sequential ring opening followed by lactonization of the α-
hydroxy amides 3 in acidic media. Thus, reaction of compound syn-3a in MeOH/H2SO4 (2:1) gave α-
hydroxy amide 8. The cyclization step was carried out using a catalytic amount of p-toluenesulfonic
acid in toluene at reflux temperature after neutralization and isolation of compound 8. In the event,
enantiomerically pure γ-butyrolactone syn-7a was isolated in good yield (73%) without epimerization of
the α position of the amide group (Table 6, entry 1). However, lactone anti-7a was obtained in low yield
when the reaction was performed with isomer anti-3a, (Table 6, entry 2). To assess scope, Passerini
adducts 3b and 3c were tested as precursors. Gratifyingly, compounds 3b and 3c were completely and
exclusively converted to γ-lactones 7 in moderate yield (Table 6, entries 3−5). Replacement of the p-
methoxyphenyl group at the nitrogen, by an aliphatic substituent such as 2-propynyl group, in Passerini
adduct syn-3d, also afforded γ-butyrolactone syn-7d (Table 6, entry 6). However, longer reaction time
for the ring opening of the β-lactam was observed.
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7
The structure and stereochemistry of γ-lactams 6 and γ-lactones 7 were assigned by NMR studies.
The cis-stereochemistry of the four-membered ring was set during the cyclization step. The cyclic
structures (by DEPT, HMQC, and COSY) and the stereochemistry (by vicinal proton couplings) of γ-
lactams 6 and γ-lactones 7 were established by NMR one- and two-dimensional techniques and
NOESY-1D experiments (see Fig 1 in Supporting information). In addition, the vicinal coupling
constants between H3, H4 and H4, H5 protons in compounds 6 are higher for anti,syn-isomers [(7.0 Hz
< 3J3,4 < 9.5 Hz); (7.9 Hz < 3J4,5< 9.1 Hz)] than for the anti,anti-isomers [(7.0 Hz < 3J3,4 < 9.5 Hz); (7.9
Hz < 3J4,5 < 9.1 Hz)] (see Table S3 in Supporting information). Analogously, for γ-lactones 7, the vicinal
coupling constants between H3, H4 and H5, H4 protons, are higher for anti,syn-isomers [(5.7 Hz < 3J3,4
8
9
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3
3
< 6.9 Hz); (4.1 Hz < J5,4< 6.7 Hz)] than for the anti,anti-isomers [(4.9 Hz < J3,4 < 5.1 Hz); (4.7 Hz <
3J5,4< 5.4 Hz)] (see Table S4 in Supporting information). Taking into account that U-3CR adducts 2 and
P-3CR adducts 3 are converted into γ-lactams 6 and γ-lactones 7, respectively, the stereochemistries of
the carbinolic stereogenic centers for compounds 2 and 3 were confirmed by comparison with well-
established five-membered rings 6 and 7.
Table 6. Synthesis of γ-butyrolactones 7 via sequential ring opening/lactonization of Passerini
adducts 3
Entry P-3CR adduct R1
R2
R3
t(h)[a] Product
Yield (%)b
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8
1
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4
5
6
syn-(+)-3a
anti-(+)-3a
syn-(+)-3b
anti-(+)-3b
syn-(+)-3c
syn-(+)-3d
PMPc
PMPc
PMPc
PMPc
PMPc
MeO t-Bu
MeO t-Bu
MeO Bn
MeO Bn
2
2
7
7
syn-(+)-7a 73
anti-(−)-7a 34
syn-(+)-7b 47
anti-(−)-7b 42
syn-(+)-7c 57
syn-(+)-7d 52
9
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59
60
PhO t-Bu 24
2-propynyl PhO t-Bu 72
aReaction progress was followed by TLC for the methanolysis step. The reaction time for
the lactonization reaction was 2 hours in all cases. Yield of pure, isolated isomers with
correct analytical and spectral data. PMP = 4-MeOC6H4
b
χ
CONCLUSION
In conclusion, firstly, organocatalyzed U-3CR between β-lactam aldehydes, amines, isocyanides and
phenyl phosphinic acid has been studied affording the corresponding adducts with moderate
diastereoselectivities and good yields. Secondly, organocatalyzed P-3CR between carbonyl β-lactams,
isocyanides and water has been described for the fist time. The scope of these multicomponent
processes has been investigated and the utility of the resulting products for the selective preparation of
highly functionalized γ-lactams and γ-lactones has been demonstrated.
EXPERIMENTAL SECTION25
General Methods. H and 13C NMR spectra were recorded in CDCl3 except otherwise stated.
1
Chemical shifts are given in ppm relative to TMS (1H, 0.0 ppm) or CDCl3 (13C, 77.0 ppm). Low and
high resolution mass spectra were performed on a QTOF LC/MS spectrometer using the electronic
impact (EI) or electrospray modes (ES) unless otherwise stated. Specific rotation [α]D is given in 10–1
deg cm2 g–1 at 20 °C, and the concentration (c) is expressed in grams per 100 mL. All commercially
available compounds were used without further purification. Flash S-2 chromatography was performed
by using silica gel 60 (230−400 mesh). Products were identified by TLC. UV light (λ = 254nm) and a
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solution of phosphomolibdic acid in EtOH (1 g of phosphomolybdic acid hydrate, 100 mL EtOH) was
used to develop the plates.
9
General Procedure for the Organocatalyzed U-3CR of aldehydes 1. Synthesis of Compounds 2.
Method A. To a solution of aldehyde 1 (1 mmol) in anhydrous dichloromethane (5 mL), the
corresponding amine (1.1 mmol), the appropriate isocyanide (1.1 mmol) and phenyl phosphinic acid
(0.1 mmol) were sequentially added at room temperature under argon atmosphere. The reaction mixture
was stirred until complete disappearances of the starting material (TLC). Then, the solvent was removed
under reduced pressure. The residue was purified by flash chromatography eluting with n-hexane/ethyl
acetate mixtures. Method B. To a solution of aldehyde 1 (1 mmol) in anhydrous dichloromethane (5
mL), methyl glycinate chlorhydrate (1.1 mmol) and triethylamine (1.1 mol) were added at room
temperature. The reaction mixture was stirred at room temperature for 1 h. Then, t-butyl isocyanide (1.1
mmol) and phenyl phosphinic acid (0.1 mmol) were added at room temperature and under argon
atmosphere. The reaction mixture was stirred at room temperature for 14h. Then, the solvent was
removed under reduced pressure. The residue was purified by flash chromatography.
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Ugi adduct 2a. Method A. From 50 mg (1.19 mmol) of aldehyde (+)-1a, compound 2a was
obtained as a mixture of isomers in a syn/anti ratio (61:39). After flash chromatography (n-hexane/ethyl
acetate, 1:1) 53 mg (61%) of the less polar compound syn-(+)-2a and 34 mg (39%) of the more polar
compound anti-(+)-2a were obtained. syn-(+)-2a. White solid; Mp: 94−95°C (n-hexane/ethyl acetate);
1
[α]D +66.0 (c 0.3, CHCl3); H NMR (300 MHz, CDCl3, 25°C): δ = 7.88 (t, J = 5.3 Hz, 1H), 7.26 (m,
5H), 7.12 (m, 2H), 6.73 (AA'XX', 2H), 5.74 (m, 1H), 5.08 (m, 2H), 5.00 (dd, J = 5.3 Hz, J = 1.3 Hz,
1H), 4.68 (d, J = 5.3 Hz, 1H), 4.47 (dd, J = 14.8, 6.3 Hz, 1H), 4.19 (dd, J = 14.8, 5.5 Hz, 1H), 3.74 (s,
13
3H), 3.65 (s, 3H), 3.40 (s, 1H), 3.29 (dd, J = 13.8, 6.4 Hz, 1H), 3.20 (dd, J = 13.7, 6.0 Hz, 1H); C
NMR (75 MHz, CDCl3, 25°C): δ = 172.8, 164.8, 156.7, 137.6, 135.7, 130.1, 128.6, 127.6, 127.4, 119.3,
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117.0, 114.2, 83.2, 59.9, 59.2, 58.8, 55.4, 51.5, 43.3; IR (KBr): ν = 3340, 1749, 1663 cm–1; HRMS
7
8
+
(ES): calcd for C23H28N3O4 [M+H]+: 410.2074; found: 410.2068. anti-(+)-2a. Colorless oil; [α]D
9
10
11
12
13
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+123.2 (c 0.4, CHCl3); 1H NMR (300 MHz, CDCl3, 25°C): δ = 8.14 (t, J = 5.6 Hz, 1H), 7.40 (AA'XX',
2H), 7.30 (m, 5H), 6.91 (AA'XX', 2H), 5.70 (m, 1H), 5.11 (dd, J = 5.0, 3.7 Hz, 1H), 4.84 (m, 2H), 4.69
(d, J = 5.1 Hz, 1H), 4.57 (dd, J = 14.9, 6.7 Hz, 1H), 4.34 (dd, J = 15.0, 5.3 Hz, 1H), 3.90 (d, J = 3.6 Hz,
13
1H), 3.81 (s, 3H), 3.47 (s, 3H), 3.24 (dd, J = 13.9, 5.4 Hz, 1H), 2.89 (dd, J = 13.9, 7.0 Hz, 1H); C
NMR (75 MHz, CDCl3, 25°C): δ = 172.0, 164.4, 156.6, 138.3, 135.9, 130.6, 128.6, 127.5, 127.3, 118.4,
117.3, 114.6, 83.8, 60.0, 58.6, 57.0, 55.4, 51.2, 43.0; IR (CHCl3): ν = 3346, 1748, 1659 cm–1; HRMS
+
(ES): calcd for C23H28N3O4 [M+H]+: 410.2074; found: 410.2076.
Ugi adduct 2b. Method A. From 60 mg (0.26 mmol) of aldehyde (+)-1a, compound 2b was
obtained as a mixture of isomers in a syn/anti ratio (63:37). After flash chromatography (n-hexane/ethyl
acetate, 1:3) 33 mg (34%) of the less polar compound syn-(+)-2b and 55 mg (58%) of the more polar
1
compound anti-(+)-2a were obtained. syn-(+)-2b. Colorless oil; [α]D +85.5 (c 0.7, CHCl3); H NMR
(300 MHz, CDCl3, 25°C): δ = 7.66 (bs, 1H), 7.38 (AA'XX', 2H), 6.88 (AA'XX', 2H), 5.63 (m, 1H), 5.02
(dd, J = 5.1, 3.6 Hz, 1H), 4.87 (m, 2H), 4.67 (d, J = 5.2 Hz, 1H), 3.79 (s, 3H), 3.72 (d, J = 3.4 Hz, 1H),
3.55 (s, 3H), 3.23 (ddt, J = 14.1, 5.4 Hz, 1.5 Hz, 1H), 2.88 (dd, J = 14.2, 6.7 Hz, 1H), 1.34 (s, 9H); 13C
NMR (75 MHz, CDCl3, 25°C): δ = 171.1, 164.4, 156.5, 136.1, 130.7, 118.4, 116.8, 114.5, 83.8, 60.1,
58.9, 57.6, 55.4, 51.3, 50.6, 28.6; IR (CHCl3): ν = 3339, 1749, 1666 cm–1; HRMS (ES): calcd for
+
C20H30N3O4 [M+H]+: 376.2231; found: 376.2244. anti-(+)-2b. Colorless oil; [α]D +70.7 (c 0.6,
CHCl3); 1H NMR (300 MHz, CDCl3, 25°C): δ = 7.50 (bs, 1H), 7.30 (AA'XX', 2H), 6.82 (AA'XX', 2H),
5.80 (m, 1H), 5.12 (m, 2H), 4.98 (d, J = 5.1 Hz, 1H), 4.66 (d, J = 5.2 Hz, 1H), 3.78 (3H, s), 3.65 (s, 3H),
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3.36 (dd, J = 14.0, 6.2 Hz, 1H), 3.20 (bs, 1H), 3.17 (dd, J = 14.3, 6.0 Hz, 1H), 1.29 (s, 9H); C NMR
(75 MHz, CDCl3, 25°C): δ = 171.6, 165.1, 156.8, 136.0, 130.4, 119.6, 116.7, 114.3, 83.2, 59.9, 59.5,
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58.7, 55.5, 51.4, 28.4, 50.6; IR (CHCl3): ν = 3332, 1750, 1668 cm–1; HRMS (ES): calcd for
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C20H30N3O4 [M+H]+: 376.2231; found: 376.2234.
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Ugi adduct 2c. Method A. From 50 mg (0.22 mmol) of aldehyde (−)-1b, compound 2c was
obtained as a mixture of isomers in a syn/anti ratio (72:28). After flash chromatography (CH2Cl2/ethyl
acetate, 3:1) 42 mg (48%) of the less polar compound syn-(+)-2c and 16 mg (18%) of the more polar
compound anti-(+)-2c were obtained. syn-(+)-2c. White solid. Mp: 108−109°C (n-hexane/ethyl acetate);
[α]D +17.4 (c 0.6, CHCl3); 1H NMR (300 MHz, CDCl3, 25°C): δ = 7.74 (bs, 1H), 7.30 (m, 7H), 7.04 (m,
3H), 5.74 (m, 2H), 5.30 (d, J = 4.9 Hz, 1H), 5.12 (m, 4H), 4.54 (dd, J = 4.9, 3.0 Hz, 1H), 4.41 (d, J = 6.0
Hz, 2H), 4.07 (ddt, J = 15.4, 5.6 Hz, 1.4 Hz, 1H), 3.60 (dd, J = 15.4, 7.0 Hz, 1H), 3.40 (d, J = 2.9 Hz,
1H), 3.25 (d, J = 6.2 Hz, 2H); 13C NMR (75 MHz, CDCl3, 25°C): δ = 171.8, 165.6, 157.3, 137.7, 135.5,
130.7, 129.7, 128.7, 127.8, 127.6, 122.6, 119.2, 117.1, 115.4, 80.8, 60.3, 59.0, 51.4, 44.4, 43.4; IR
+
(CHCl3): ν = 3319, 1757, 1656 cm–1; HRMS (ES): calcd for C24H28N3O3 [M+H]+: 406.2125; found:
406.2106. anti-(+)-2c. White solid. Mp: 125−126°C (n-hexane/ethyl acetate); [α]D +50.7 (c 0.4,
1
CHCl3); H NMR (300 MHz, CDCl3, 25°C): δ = 7.77 (t, J = 5.5 Hz, 1H), 7.29 (m, 5H), 7.17 (m, 2H),
7.03 (m, 3H), 5.79 (m, 2H), 5.33 (d, J = 4.9 Hz, 1H), 5.21 (m, 4H), 4.61 (t, J = 4.9 Hz, 1H), 4.40 (dd, J
= 14.2, 6.3 Hz, 1H), 4.25 (ddt, J = 15.4, 5.4, 1.4 Hz, 1H), 4.11 (dd, J = 14.8, 5.6 Hz, 1H), 3.65 (d, J =
4.8 Hz, 1H), 3.63 (dd, J = 15.2, 7.4 Hz, 1H), 3.38 (dd, J = 13.9, 6.0 Hz, 1H), 3.25 (dd. J =13.9, 6.2 Hz,
1H); 13C NMR (75 MHz, CDCl3, 25°C): δ = 171.0, 165.7, 157.2, 137.8, 135.7, 130.6, 129.6, 128.6,
127.7, 127.4, 122.7, 119.8, 117.3, 115.6, 81.1, 59.9, 58.9, 51.7, 43.7, 43.2; IR (CHCl3): ν = 3332, 1755,
+
1658 cm–1; HRMS (ES): calcd for C24H28N3O3 [M+H]+: 406.2125; found: 406.2121.
Ugi adduct 2d. Method B. From 89 mg (0.27 mmol) of aldehyde (−)-1c, compound 2d was
obtained as a mixture of isomers in a syn/anti ratio (70:30). After flash chromatography (n-hexane/ethyl
acetate, 1:3) 100 mg (74%) of an inseparable mixture of isomers syn-2d and anti-2d was obtained. syn-
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2d. H NMR (300 MHz, CDCl3, 25°C): δ = 7.86 (AA'BB', 2H), 7.74 (AA'BB', 2H), 7.33 (m, 5H), 6.24
(bs, 1H), 5.45 (d, J = 5.3 Hz, 1H), 4.73 (d, J = 15.2 Hz, 1H), 4.60 (d, J = 15.2 Hz, 1H), 4.04 (dd, J = 7.8,
5.3 Hz, 1H), 3.64 (s, 3H), 3.29 (d, J = 7.9 Hz, 1H), 3.09 (d, J = 17.2 Hz, 1H), 2.97 (d, J = 17.1 Hz, 1H),
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2.03 (bs, 1H), 1.00 (s, 9H); C NMR (75 MHz, CDCl3, 25°C): δ = 171.7, 169.4, 164.6, 135.8, 134.5,
131.9, 128.9, 128.2, 127.9, 123.7, 62.9, 59.6, 55.6, 51.8, 51.0, 48.0, 46.1, 28.2; HRMS (ES): calcd for
+
1
C27H31N4O6 [M+H]+: 507.2238; found: 507.2255. anti-2d. H NMR (300 MHz, CDCl3, 25°C): δ =
7.86 (2H, AA'BB'), 7.74 (AA'BB', 2H), 7.33 (m, 5H), 6.49 (bs, 1H), 5.37 (d, J = 5.3 Hz, 1H), 4.68 (d, J =
15.2 Hz, 1H), 4.40 (d, J = 15.0 Hz, 1H), 4.11 (dd, J = 6.9, 5.4 Hz, 1H), 3.45 (s, 3H), 3.26 (d, J = 7.2 Hz,
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1H), 3.00 (d, J = 17.2 Hz, 1H), 2.85 (d, J = 17.4 Hz, 1H), 2.03 (bs, 1H), 1.13 (s, 9H); C NMR (75
MHz, CDCl3, 25°C): δ = 171.4, 167.4, 164.3, 135.5, 134.4, 131.9, 129.0, 128.3, 128.0, 123.7, 61.8,
58.7, 56.4, 51.6, 51.1, 48.4, 45.6, 28.3.
Ugi adduct 2e. Method A. From 50 mg (0.21 mmol) of aldehyde (+)-1a, compound 2e was
obtained as a mixture of isomers in a syn/anti ratio (64:36). After flash chromatography (n-hexane/ethyl
acetate, 1:1) 70 mg (74%) of an inseparable mixture of isomers syn-2e and anti-2e was obtained. syn-2e.
1H NMR (300 MHz, CDCl3, 25°C): δ = 7.12 (m, 2H), 7.09 (AA'XX', 2H), 6.68 (AA´XX´, 2H), 6.58 (m,
2H), 5.19 (bs, 1H), 4.76 (d, J = 5.1 Hz, 1H), 4.44 (d, J = 2.6 Hz, 1H), 3.74 (s, 3H), 3.671 (s, 3H), 3.669
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(s, 3H), 1.36 (s, 9H); C NMR (75 MHz, CDCl3, 25°C): δ = 170.0, 163.6, 156.2, 153.1, 140.2, 130.0,
118.5, 115.9, 114.5, 113.9, 83.7, 60.3, 58.9, 57.9, 55.6, 55.3, 51.0, 28.6. HRMS (ES): calcd for
+
1
C24H32N3O5 [M+H]+: 442.2336; found: 442.2336. anti-2e. H NMR (300 MHz, CDCl3, 25°C): δ =
7.38 (AA'XX', 2H), 6.85 (AA'XX', 2H), 6.77 (AA'XX', 2H), 6.58 (m, 2H), 5.09 (dd, J = 5.2, 1.7 Hz, 1H),
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4.68 (d, J = 5.3 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.67 (m, 1H), 3.43 (s, 3H), 1.28 (s, 9H); C NMR
(75 MHz, CDCl3, 25°C): δ = 171.0, 165.1, 156.8, 153.3, 140.6, 130.1, 119.5, 115.8, 114.5, 114.3, 82.9,
59.5, 58.2, 59.0, 55.5, 55.4, 51.0, 28.3.
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Ugi adduct 2f. Method A. From 53 mg (0.14 mmol) of aldehyde (+)-1d, compound 2f was obtained
as a mixture of isomers in a syn/anti ratio (70:30). After flash chromatography (n-hexane/ethyl acetate,
1:1) 21 mg (28%) of the less polar compound anti-(+)-2f and 50 mg (64%) of the more polar compound
syn-(+)-2f were obtained. syn-(+)-2f. White solid. Mp: 141−143°C (n-hexane/ethyl acetate); [α]D +82.7
(c 0.6, CHCl3); 1H NMR (300 MHz, CDCl3, 25°C): δ = 7.55 (t, J = 5.6 Hz, 1H), 7.30 (m, 5H), 7.08 (m,
7H), 6.69 (AA'XX', 2H), 6.51 (AA'XX', 2H), 6.47 (AA'XX', 2H), 5.51 (d, J = 5.0 Hz, 1H), 5.40 (dd, J =
4.8, 3.5 Hz, 1H), 4.72 (d, J = 3.4 Hz, 1H), 4.34 (dd, J = 14.5, 5.6 Hz, 1H), 4.34 (dd, J = 14.5, 5.6 Hz,
1H), 4.20 (dd, J = 14.6, 6.0 Hz, 1H), 3.65 (s, 3H), 3.74 (s, 3H); 13C NMR (75 MHz, CDCl3, 25°C): δ =
170.6, 162.2, 157.2, 156.6, 153.4, 140.1, 137.6, 129.7, 129.6, 128.7, 127.8, 127.5, 123.1, 118.8, 116.2,
116.1, 114.6, 114.2, 81.1, 58.2, 59.0, 55.6, 55.4, 43.4; IR (KBr): ν = 3374, 1750, 1661 cm–1; HRMS
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(ES): calcd for C32H32N3O5 [M+H]+: 538.2336; found: 538.2311. anti-(+)-2f. White solid. Mp:
150−151°C (n-hexane/ethyl acetate); [α]D +66.2 (c 0.2, CHCl3); 1H NMR (300 MHz, CDCl3, 25°C): δ =
7.59 (t, J = 5.6 Hz, 1H), 7.36 (AA'XX', 2H), 7.25 (m, 3H), 7.19 (t, J = 8.0 Hz, 2H), 7.08 (m, 2H), 6.96 (t,
J = 7.3 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.74 (AA'XX', 2H), 6.65 (AA'XX', 2H), 6.57 (AA'XX', 2H),
5.53 (d, J = 5.1 Hz, 1H), 5.43 (d, J = 5.3 Hz, 1H), 4.44 (dd, J = 14.8, 6.3 Hz, 1H), 4.36 (dd, J = 14.9, 5.7
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Hz, 1H), 4.08 (s, 1H), 3.77 (s, 3H), 3.75 (s, 3H); C NMR (75 MHz, CDCl3, 25°C): δ = 172.1, 163.4,
157.1, 156.8, 153.7, 140.5, 137.4, 129.9, 129.5, 128.6, 127.8, 127.5, 122.3, 119.3, 116.1, 115.1, 114.8,
114.6, 79.3, 58.44, 58.42, 55.8, 55.5, 43.6; IR (KBr): ν = 3350, 1754, 1664 cm–1; HRMS (ES): calcd for
+
C32H32N3O5 [M+H]+: 538.2336; found: 538.2317.
Ugi adduct 2g. Method A. From 58 mg (0.25 mmol) of aldehyde (−)-1b, compound 2g was
obtained as a mixture of isomers in a syn/anti ratio (68:32). After flash chromatography (diethyl ether)
24 mg (21%) of the less polar compound anti-(+)-2g and 52 mg (46%) of the more polar compound syn-
(+)-2g were obtained. syn-(+)-2g. Yellowish solid. Mp: 193−194°C (n-hexane/ethyl acetate); [α]D +5.8
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(c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3, 25°C): δ = 8.11 (AA'XX', 2H), 7.25 (m, 2H), 7.02 (m, 1H),
6.88 (m, 2H), 6.67 (AA'XX', 2H), 6.51 (bs, 1H), 5.77 (m, 1H), 5.39 (d, J = 5.1 Hz, 1H), 5.25 (m, 3H),
4.56 (t, J = 5.0 Hz, 1H), 4.21(dd, J = 6.3, 5.3 Hz, 1H), 4.15 (ddt, J = 15.3, 5.6, 1.2 Hz, 1H), 3.51 (dd, J =
15.3, 7.2 Hz, 1H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3, 25°C): δ = 168.1, 165.9, 156.5, 152.0,
139.8, 130.4, 129.7, 126.1, 122.8, 120.1, 115.1, 112.8, 80.1, 58.0, 57.1, 51.8, 44.5, 28.5; IR (KBr): ν =
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3301, 1755 cm–1; HRMS (ES): calcd for C24H29N4O5 [M+H]+: 453.2132; found: 453.2133.
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anti-(+)-2g. Yellowish solid. Mp: 189−190°C (n-hexane/ethyl acetate); [α]D +63.4 (c 0.1, CHCl3) H
NMR (300 MHz, CDCl3, 25°C): δ = 8.15 (AA'XX', 2H), 7.39 (m, 2H), 7.14 (m, 3H), 6.62 (AA'XX', 2H),
6.58 (bs, 1H), 5.60 (m, 2H), 5.43 (d, J = 5.0 Hz, 1H), 5.19 (m, 2H), 4.59 (dd, J = 5.0, 2.6 Hz, 1H), 4.43
(dd, J = 7.8, 2.6 Hz, 1H), 4.03 (ddt, J = 15.4, 5.7, 1.3 Hz, 1H), 3.55 (dd, J = 15.3, 7.2 Hz, 1H), 1.29 (s,
9H); 13C NMR (75 MHz, CDCl3, 25°C): δ = 166.7, 165.0, 156.6, 151.2, 139.8, 130.4, 130.0, 126.5,
123.6, 120.2, 115.8, 112.2, 81.0, 58.3, 56.3, 51.8, 43.8, 28.5; IR (KBr): ν = 3300, 1761 cm–1; HRMS
+
(ES): calcd for C24H29N4O5 [M+H]+: 453.2132; found: 453.2126.
General Procedure for the Organocatalyzed P-3CR of aldehydes 1. Synthesis of Compounds 3.
To a solution of aldehyde 1 (1 mmol) in anhydrous dichloromethane (5 mL), water (1.1 mmol), the
appropriate isocyanide (1.1 mmol) and phenyl phosphinic acid (0.1 mmol) were sequentially added at
room temperature under argon atmosphere. The reaction mixture was stirred until complete
disappearances of the starting material (TLC). Then, the solvent was removed under reduced pressure.
The residue was purified by flash chromatography eluting with n-hexane/ethyl acetate mixtures.
Passerini adduct 3a. From 100 mg (0.42 mmol) of aldehyde (+)-1a, compound 3a was obtained as
a mixture of isomers in a syn/anti ratio (60:40). After flash chromatography (n-hexane/ethyl acetate,
1:2) 57 mg (40%) of the less polar compound anti-(+)-3a and 86 mg (60%) of the more polar compound
syn-(+)-3a were obtained. syn-(+)-3a. White solid. Mp: 116−117°C (n-hexane/ethyl acetate); [α]D +45.2
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(c 0.2, CHCl3). 1H NMR (300 MHz, CDCl3, 25°C): δ = 7.40 (AA'XX, 2H,), 6.80 (AA'XX', 2H), 6.59 (bs,
1H), 4.94 (dd, J = 5.2, 1.2 Hz, 1H), 4.71 (d, J = 5.2 Hz, 1H), 4.27 (d, J = 1.2 Hz, 1H), 3.76 (s, 3H), 3.70
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(s, 3H), 1.22 (s, 9H); C NMR (75 MHz, CDCl3, 25°C): δ = 169.2, 164.2, 156.7, 130.2, 120.0, 114.2,
82.8, 69.2, 60.0, 58.2, 55.4, 50.9, 28.4; IR (KBr): ν = 3394, 1747 cm–1; HRMS (ES): calcd for
+
C17H25N2O5 [M+H]+: 337.1758; found: 337.1765. anti-(+)-3a. White solid. Mp: 158−159°C (n-
hexane/ethyl acetate); [α]D +83.9 (c 0.4, CHCl3). 1H NMR (300 MHz, CDCl3, 25°C): δ = 7.41 (AA'XX',
2H), 6.83 (m, 1H), 6.85 (AA'XX', 2H), 4.80 (dd, J = 5.2, 1.6 Hz, 1H), 4.73 (d, J = 5.2 Hz, 1H), 4.48 (d, J
= 1.1 Hz, 1H), 3.87 (bs, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 1.33 (s, 9H); 13C NMR (75 MHz, CDCl3, 25°C):
δ = 169.4, 163.5, 156.6, 130.2, 118.9, 114.4, 83.2, 68.8, 60.0, 59.5, 55.4, 51.4, 28.6; IR (KBr): ν = 3393,
+
1747, 1664 cm–1; HRMS (ES): calcd for C17H25N2O5 [M+H]+: 337.1758; found: 337.1757.
Passerini adduct 3b. From 67 mg (0.22 mmol) of aldehyde (+)-1a, compound 3b was obtained as a
mixture of isomers in a syn/anti ratio (65:35). After flash chromatography (n-hexane/ethyl acetate, 1:1)
53 mg (59%) of the less polar compound syn-(+)-3b and 29 mg (32%) of the more polar compound
anti-(+)-3b were obtained. syn-(+)-3b. White solid; Mp: 167−169°C (n-hexane/ethyl acetate); [α]D
1
+72.5 (c 1.4, CHCl3). H NMR (300 MHz, CDCl3, 25°C): δ = 7.45 (AA'XX', 2H), 7.34 (m, 2H), 7.06
(m, 3H), 6.83 (AA'XX', 2H), 6.64 (bs, 1H), 5.45 (d, J = 5.1 Hz, 1H), 5.20 (d, J = 5.6 Hz, 1H), 4.41 (d, J
= 4.0 Hz, 1H), 3.78 (s, 3H), 3.13 (d, J = 4.2 Hz, 1H), 1.25 (s, 9H); 13C NMR (75 MHz, CDCl3, 25°C): δ
= 169.2, 162.7, 156.9, 156.8, 130.2, 129.9, 123.2, 120.0, 115.9, 114.3, 80.1, 68.8, 58.5, 55.4, 51.0, 28.4;
+
IR (KBr): ν = 3390, 1751, 1664 cm–1; HRMS (ES): calcd for C22H27N2O5 [M+H]+: 399.1914; found:
399.1927. anti-(+)-3b. White solid; Mp: 127−128°C (n-hexane/ethyl acetate); [α]D +108.2 (c 0.6,
1
CHCl3). H NMR (300 MHz, CDCl3, 25°C): δ = 7.47 (AA'XX', 2H), 7.35 (m, 2H), 7.12 (m, 3H), 6.88
(AA'XX', 2H), 6.76 (bs, 1H), 5.48 (d, J = 5.3 Hz, 1H), 5.00 (dd, J = 5.3, 1.8 Hz, 1H), 4.61 (s, 1H), 3.79
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(s, 3H), 1.26 (s, 9H); C NMR (75 MHz, CDCl3, 25°C): δ = 168.8, 162.2, 156.8, 156.7, 130.0, 129.9,
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HRMS (ES): calcd for C22H27N2O5 [M+H]+: 399.1914; found: 399.1897.
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Passerini adduct 3c. From 103 mg (0.44 mmol) of aldehyde (+)-1a, compound 3c was obtained as
a mixture of isomers in a syn/anti ratio (60:40). After flash chromatography (n-hexane/ethyl acetate,
1:2) 57 mg (35%) of the less polar compound anti-(+)-3c and 86 mg (53%) of the more polar compound
syn-(+)-3c were obtained. syn-(+)-3c. White solid; Mp: 157−159°C (n-hexane/ethyl acetate); [α]D +67.3
(c 0.5, CHCl3). 1H NMR (300 MHz, CDCl3, 25°C): δ = 7.45 (AA'XX', 2H), 7.34 (m, 2H), 7.06 (m, 3H),
6.83 (AA'XX', 2H), 6.64 (bs, 1H), 5.45 (d, J = 5.1 Hz, 1H), 5.20 (d, J = 5.6 Hz, 1H), 4.41 (d, J = 4.0 Hz,
1H), 3.78 (s, 3H), 3.13 (d, J = 4.2 Hz, 1H), 1.25 (s, 9H); 13C NMR (75 MHz, CDCl3, 25°C): δ = 169.2,
162.7, 156.9, 156.8, 130.2, 129.9, 123.2, 120.0, 115.9, 114.3, 68.8, 58.5, 55.4, 51.0, 28.4; IR (KBr): ν =
+
3295, 1732, 1652 cm–1; HRMS (ES): calcd for C20H23N2O5 [M+H]+: 371.1601; found: 371.1608. anti-
1
(+)-3c. White solid; Mp: 135−136°C (n-hexane/ethyl acetate); [α]D +107.6 (c 0.5, CHCl3). H NMR
(300 MHz, CDCl3, 25°C): δ = 7.39 (AA'XX', 2H), 7.30 (m, 5H), 7.20 (t, J = 5.6 Hz, 1H), 6.88 (AA'XX',
2H), 4.95 (dd, J = 5.0, 2.6 Hz, 1H), 4.75 (d, J = 5.1 Hz, 1H), 4.69 (s, 1H), 4.58 (dd, J = 14.8, 6.4 Hz,
13
1H), 4.38 (dd, J = 14.8, 5.4 Hz, 1H), 3.79 (s 3H), 3.56 (s, 3H); C NMR (75 MHz, CDCl3, 25°C): δ =
171.0, 163.5, 156.7, 137.7, 129.8, 128.6, 127.7, 127.6, 118.9, 114.5, 83.7, 68.8, 60.0, 58.3, 55.4, 43.2;
+
IR (KBr): ν = 3354, 1746, 1656 cm–1; HRMS (ES): calcd for C20H23N2O5 [M+H]+: 371.1601; found:
371.1583.
Passerini adduct 3d. From 51 mg (0.15 mmol) of aldehyde (−)-1c, compound 3d was obtained as a
mixture of isomers in a syn/anti ratio (55:45). After flash chromatography (diethyl ether) 25 mg (37%)
of the less polar compound syn-(+)-3d and 20 mg (31%) of the more polar compound anti-(+)-3d were
1
obtained. syn-(−)-3d. Colorless oil; [α]D −6.5 (c 0.9, CHCl3). H NMR (300 MHz, CDCl3, 25°C): δ =
7.88 (AA'BB', 2H), 7.77 (AA'BB', 2H), 7.35 (m, 5H), 6.54 (bs, 1H), 5.50 (d, J = 5.4 Hz, 1H), 4.72 (d, J =
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15.2 Hz, 1H), 4.64 (dd, J = 5.5, 3.4 Hz, 1H), 4.31 (d, J = 15.1 Hz, 1H), 4.03 (t, J = 3.9 Hz, 1H), 3.81 (d,
J = 4.5 Hz, 1H), 1.27 (s, 9H); 13C NMR (75 MHz, CDCl3, 25°C): δ = 169.3, 167.9, 164.1, 135.5, 134.7,
131.5, 129.0, 128.2, 128.0, 124.0, 68.9, 59.3, 56.0, 51.0, 46.4, 28.5; IR (CHCl3): ν = 3384, 1760, 1720,
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1670 cm–1; HRMS (ES): calcd for C24H26N3O5 [M+H]+: 436.1867; found: 436.1867. anti-(+)-3d.
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Colorless oil; [α]D +18.2 (c 0.6, CHCl3). H NMR (300 MHz, CDCl3, 25°C): δ = 7.87 (AA'BB', 2H),
7.78 (AA'BB', 2H), 7.36 (m, 5H), 6.21 (bs, 1H), 5.50 (d, J = 5.3 Hz, 1H), 4.75 (d, J = 14.9 Hz, 1H), 4.40
(t, J = 5.2 Hz, 1H), 4.39 (d, J = 15.3 Hz, 1H), 4.17 (dd, J = 7.8, 5.5 Hz, 1H), 3.76 (d, J = 7.8 Hz, 1H),
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0.95 (s, 9H); C NMR (75 MHz, CDCl3, 25°C): δ = 169.3, 163.7, 134.8, 134.7, 131.6, 129.2, 128.3,
128.3, 123.9, 68.5, 58.6, 55.5, 50.8, 45.7, 28.1; IR (CHCl3): ν = 3382, 1761, 1722, 1668 cm–1; HRMS
(ES): calcd for C24H26N3O5 [M+H]+: 436.1867; found: 436.1872.
+
Passerini adduct 3e. From 81 mg (0.36 mmol) of aldehyde (+)-1e, compound 3e was obtained as a
mixture of isomers in a syn/anti ratio (70:30). After flash chromatography (n-hexane/ethyl acetate, 3:2)
78 mg (67%) of the less polar compound syn-(+)-3e and 34 mg (29%) of the more polar compound anti-
(+)-3e were obtained. syn-(+)-3e. White solid; Mp: 137−138°C (n-hexane/ethyl acetate); [α]D +39.6 (c
0.5, CHCl3). 1H NMR (300 MHz, CDCl3, 25°C): δ = 7.34 (m, 2H), 7.10 (m, 3H), 6.70 (bs, 1H), 5.35 (d,
J = 5.0 Hz, 1H), 4.59 (dd, J = 5.0, 3.1 Hz, 1H), 4.40 (d, J = 3.1 Hz, 1H), 4.36 (dd, J = 17.8, 2.6 Hz, 1H),
13
3.85 (dd, J = 17.7, J = 2.5 Hz, 1H), 2.31 (t, J = 2.5 Hz, 1H), 1.40 (s, 9H); C NMR (75 MHz, CDCl3,
25°C): δ = 168.7, 164.7, 156.6, 129.9, 123.3, 115.8, 80.8, 76.1, 73.1, 69.4, 58.6, 51.3, 30.9, 28.6; IR
(KBr): ν = 3297, 3384, 1763, 1666 cm–1; HRMS (ES): calcd for C18H23N2O4 [M+H]+: 331.1652;
+
found: 331.1652. anti-(+)-3e. White solid; Mp: 88−90°C (n-hexane/ethyl acetate); [α]D +86.4 (c 0.8,
CHCl3). 1H NMR (300 MHz, CDCl3, 25°C): δ = 7.33 (m, 2H), 7.09 (m, 3H), 6.72 (bs, 1H), 5.37 (d, J =
5.0 Hz, 1H), 4.60 (dd, J = 4.8, 3.4 Hz, 1H), 4.50 (d, J = 3.1 Hz, 1H), 4.36 (dd, J = 17.8, 2.6 Hz, 1H),
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25°C): δ = 169.2, 164.8, 156.7, 129.8, 123.3, 115.9, 81.5, 75.9, 73.3, 69.7, 59.1, 51.4, 30.4, 28.5; IR
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+
(KBr): ν = 3295, 3388, 1761, 1660 cm–1; HRMS (ES): calcd for C18H23N2O4 [M+H]+: 331.1652;
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found: 331.1665.
General Procedure for the Organocatalyzed P-3CR of ketones 4. Synthesis of Compounds 5.
To a solution of ketone 4 (1 mmol) in anhydrous dichloromethane (5 mL), water (1.1 mmol), the
appropriate isocyanide (1.1 mmol) and phenyl phosphinic acid (0.1 mmol) were sequentially added at
room temperature under argon atmosphere. The reaction mixture was stirred until complete
disappearances of the starting material (TLC). Then, the solvent was removed under reduced pressure.
The residue was purified by flash chromatography eluting with n-hexane/ethyl acetate mixtures.
Passerini adduct syn-(−)-5a. From 44 mg (0.15 mmmol) of azetidine-2,3-dione (+)-4a, 50 mg
(78%) of compound syn-(−)-5a was obtained as a white solid after purification by flash chromatography
(n-hexane/ethyl acetate, 2:1).26
Passerini adduct syn-(−)-5b. From 60 mg (0.22 mmmol) of azetidine-2,3-dione (−)-4b, 66 mg
(80%) of compound syn-(−)-5b was obtained as a white solid after purification by flash chromatography
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(n-hexane/ethyl acetate, 1:1). Mp: 148−149°C (n-hexane/ethyl acetate); [α]D −79.7 (c 2.0, CHCl3); H
NMR (300 MHz, CDCl3, 25°C): δ = 7.44 (m, 2H), 7.30 (m, 8H), 6.89 (t, J = 5.8 Hz, 1H), 5.47 (bs, 1H),
5.02 (d, J = 15.2 Hz, 1H), 4.48 (dd, J =14.8, 6.1 Hz, 1H), 4.36 (m, 2H), 4.24 (d, J = 15.1 Hz, 1H), 4.10
(dd, J = 9.1, 7.2 Hz, 1H), 3.94 (d, J = 5.3 Hz, 1H), 3.64 (dd, J =9.1, 4.4 Hz, 1H), 1.41 (s, 3H), 1.34 (s,
13
3H); C NMR (75 MHz, CDCl3, 25°C): δ = 167.4, 167.3, 137.4, 134.3, 128.74, 128.69, 128.4, 127.8,
127.6, 127.5, 110.3, 85.2, 75.1, 66.3, 63.6, 45.5, 43.3, 26.3, 24.9; IR (KBr): ν = 3315, 1745, 1671 cm–1;
HRMS (ES): calcd for C23H27N2O5 [M+H]+: 411.1914; found: 411.1930.
+
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Passerini adduct syn-(−)-5c. From 32 mg (0.11 mmmol) of azetidine-2,3-dione (+)-4a, 21 mg
(48%) of compound syn-(−)-5c was obtained as a white solid after purification by flash chromatography
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(n-hexane/ethyl acetate, 1:1). Mp: 154−156°C (n-hexane/ethyl acetate); [α]D −7.0 (c 0.6, CHCl3); H
NMR (300 MHz, CDCl3, 25°C): δ = 7.49 (AA'XX', 2H), 6.86 (AA'XX', 2H), 6.56 (bs, 1H), 5.08 (bs,
1H), 4.60 (d, J = 4.8 Hz, 1H), 4.43 (td, J = 6.7, 4.9 Hz, 1H), 4.20 (dd, J =8.9, 6.7 Hz, 1H), 3.79 (s, 3H),
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3.80 (dd, J = 8.8, 6.9 Hz, 1H), 1.41 (s, 3H), 1.39 (s, 9H), 1.37 (s, 3H); C NMR (75 MHz, CDCl3,
25°C): δ = 166.0, 164.7, 157.1, 130.0, 120.6, 114.0, 110.2, 84.9, 75.7, 66.5, 64.9, 55.4, 51.7, 28.6, 26.3,
+
25.2; IR (KBr): ν = 3243, 1759, 1658 cm–1; HRMS (ES): calcd for C20H29N2O6 [M+H]+: 393.2020;
found: 393.2034.
Passerini adduct syn-(−)-5d. From 55 mg (0.24 mmmol) of azetidine-2,3-dione (−)-4c, 56 mg
(71%) of compound syn-(−)-5d was obtained as a white solid after purification by flash chromatography
1
(n-hexane/ethyl acetate, 1:1). Mp: 130−132°C (n-hexane/ethyl acetate) [α]D −106.8 (c 0.3, CHCl3); H
NMR (300 MHz, CDCl3, 25°C): δ = 6.57 (bs, 1H), 5.85 (m, 1H), 5.36 (m, 2H), 4.96 (bs, 1H), 4.34 (m,
2H), 4.17 (dd, J = 8.9, 7.2 Hz, 1H), 4.05 (d, J = 4.5 Hz, 1H), 3.82 (dd, J = 9.1, 4.5 Hz, 1H), 3.70 (dd, J
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=15.7, 7.5 Hz, 1H), 1.39 (s, 9H), 1.38 (s, 3H), 1.36 (s, 3H); C NMR (75 MHz, CDCl3, 25°C): δ =
167.4, 166.1, 130.9, 119.1, 110.2, 85.3, 75.2, 66.4, 63.7, 51.4, 44.1, 28.6, 26.5, 25.0; IR (KBr): ν =
+
3403, 1746, 1679 cm–1; HRMS (ES): calcd for C16H27N2O5 [M+H]+: 327.1914; found: 327.1914.
Passerini adduct syn-(+)-5e. From 42 mg (0.14 mmmol) of azetidine-2,3-dione (+)-4a, 27 mg
(45%) of compound syn-(+)-5e was obtained as a white solid after purification by flash chromatography
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(n-hexane/ethyl acetate, 1:1). Mp: 123−124°C (n-hexane/ethyl acetate); [α]D +5.8 (c 0.2, CHCl3). H
NMR (300 MHz, CDCl3, 25°C): δ = 7.57 (AA'XX', 2H), 6.87 (AA'XX', 2H), 6.37 (bs, 1H), 4.56 (d, J =
6.6 Hz, 1H), 4.45 (q, J = 6.6 Hz, 1H), 4.20 (q, J = 7.0 Hz, 2H), 4.22 (m, 2H), 3.96 (dd, J = 18.0, 5.0 Hz,
1H), 3.80 (s, 3H), 3.79 (m, 1H), 1.46 (s, 3H), 1.38 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
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CDCl3, 25°C): δ = 170.1, 167.9, 164.5, 157.2, 130.0, 120.7, 114.0, 110.1, 84.1, 76.3, 66.7, 66.3, 61.7,
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55.4, 41.1, 26.5, 25.1, 14.0; IR (KBr): ν = 3346, 1750, 1680 cm–1; HRMS (ES): calcd for C20H30N3O8
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[M+NH4]+: 440.2027; found: 440.2045.
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General Procedure for the Ring Expansion of Ugi Adducts 2. Synthesis of functionalized γ-
lactams 6. Method A. To a solution of Ugi adduct 2 (1 mmol) in methanol (23 mL), sodium methoxide
(1 mmol), was added in small portions at room temperature under argon atmosphere. The reaction
mixture was stirred until complete disappearances of the starting material (TLC). Then, the solvent was
removed under reduced pressure. The residue was purified by flash chromatography eluting with n-
hexane/ethyl acetate mixtures. Method B. To a solution of Ugi adduct syn-(+)-2a (1 mmol) in methanol
(2 mL), sulfuric acid (cc.) (12 mL) was added at room temperature. The reaction mixture was dtirred for
54 h. Then, the mixture was neutralized with NaHCO3 (sat.) (50 mL). The methanol was removed under
reduced pressure and the mixture was extracted with ethyl acetate (5 x 100 mL). The organic layer was
dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash
chromatography eluting with n-hexane/ethyl acetate mixtures.
Functionalized γ-lactam syn-(+)-6a. Method A. From 46 mg (0.11 mmmol) of compound syn-(+)-
2a, 39 mg (84%) of compound syn-(+)-6a was obtained as a colorless oil after purification by flash
chromatography (n-hexane/ethyl acetate, 1:3). Method B. From 51 mg (0.12 mmmol) of compound
syn-(+)-2a, 11 mg (22%) of compound syn-(+)-6a was obtained as a colorless oil after purification by
1
flash chromatography (n-hexane/ethyl acetate, 1:3). [α]D +155.8 (c 0.3, CHCl3); H NMR (300 MHz,
CDCl3, 25°C): δ =7.82 (bs, 1H), 7.22 (m, 3H), 7.11 (m, 2H), 6.79 (AA'BB', 2H), 6.75 (AA'BB', 2H),
5.78 (m, 1H), 5.20 (m, 2H), 4.58 (d, J = 7.4 Hz, 1H), 4.44 (dd, J = 15.2, 6.4 Hz, 1H), 4.32 (d, J = 9.1 Hz,
1H), 4.27 (dd, J =15.2, 5.3 Hz, 1H), 4.18 (dd, J = 9.0, 7.3 Hz, 1H), 4.15 (m, 1H), 3.73 (s, 3H), 3.63 (s,
3H), 3.58 (dd J = 15.7, 6.9 Hz, 1H); 13C NMR (75 MHz, CDCl3, 25°C): δ = 171.3, 168.3, 152.8, 140.2,
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136.9, 131.7, 128.7, 127.8, 127.7, 119.3, 115.1, 114.4, 81.1, 61.1, 59.2, 57.5, 55.6, 45.0, 43.9; IR
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+
(CHCl3): ν = 3317, 1689 cm–1; HRMS (ES): calcd for C23H28N3O4 [M+H]+: 410.2074; found:
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410.2067.
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Functionalized γ-lactam anti-(−)-6a. Method A. From 44 mg (0.11 mmmol) of compound anti-
(+)-2a, 27 mg (60%) of compound anti-(−)-6a was obtained as a white solid after purification by flash
chromatography (n-hexane/ethyl acetate, 1:3). Mp: 163−165°C (n-hexane/ethyl acetate); [α]D −9.2 (c
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0.3, CHCl3); H NMR (300 MHz, CDCl3, 25°C): δ = 8.01 (bs, 1H), 7.26 (m, 5H), 6.78 (AA'BB', 2H),
6.73 (AA'BB', 2H), 5.74 (m, 1H), 5.15 (m, 2H), 4.49 (dd, J = 14.9, 6.1 Hz, 1H), 4.39 (m, 1H), 4.36 (dd,
J =14.8, 5.9 Hz, 1H), 4.09 (t, J = 5.7 Hz, 1H), 4.03 (d, J = 5.4 Hz, 1H), 3.94 (d, J = 6.1 Hz, 1H), 3.74 (s,
3H), 3.56 (s, 3H), 3.44 (dd, J = 15.5, 7.4 Hz, 1H), 2.91 (bs, 1H); 13C NMR (75 MHz, CDCl3, 25°C): δ =
171.1, 168.9, 153.5, 138.9, 137.4, 130.8, 128.7, 127.8, 127.7, 119.9, 115.8, 115.0, 83.1, 65.9, 58.7, 58.3,
55.6, 44.5, 43.7; IR (KBr): ν = 3364, 3277, 1699, 1657 cm–1; HRMS (ES): calcd for C23H28N3O4
+
[M+H]+: 410.2074; found: 410.2077.
Functionalized γ-lactam syn-(+)-6b. Method A. From 31 mg (0.08 mmmol) of compound syn-
(+)-2b, 25 mg (82%) of compound syn-(+)-6b was obtained as a colorless oil after purification by flash
chromatography (n-hexane/ethyl acetate, 1:3). [α]D +139.6 (c 0.2, CHCl3); H NMR (300 MHz, d6-
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acetone, 25°C): δ = 6.80 (AA'BB', 2H), 6.74 (AA'BB', 2H), 5.77 (m, 1H), 5.21 (m, 2H), 4.45 (d, J = 7.3
Hz, 1H), 4.25 (d, J = 8.8 Hz, 1H), 4.11 (m, 1H), 4.07 (ddt, J = 15.2, 5.5 Hz, 1.5 Hz, 1H), 3.72 (s, 3H),
3.62 (s, 3H), 3.59 (dd, J = 15.6, 6.4 Hz, 1H), 1.19 (s, 9H); 13C NMR (75 MHz, CDCl3, 25°C): δ = 171.3,
167.3, 152.8, 140.3, 132.1, 119.2, 115.2, 114.4, 81.0, 61.5, 59.2, 57.2, 55.8, 52.0, 45.0, 28.3; IR
(CHCl3): ν = 3337, 1689 cm–1; HRMS (ES): calcd for C20H30N3O4 [M+H]+: 376.2231; found:
+
376.2235.
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